Decker Martina, Arand Michael, Cronin Annette
Institute of Pharmacology and Toxicology, University of Zürich, Winterthurer Str. 190, 8057 Zurich, Switzerland.
Arch Toxicol. 2009 Apr;83(4):297-318. doi: 10.1007/s00204-009-0416-0. Epub 2009 Apr 2.
Epoxide hydrolases catalyse the hydrolysis of electrophilic--and therefore potentially genotoxic--epoxides to the corresponding less reactive vicinal diols, which explains the classification of epoxide hydrolases as typical detoxifying enzymes. The best example is mammalian microsomal epoxide hydrolase (mEH)-an enzyme prone to detoxification-due to a high expression level in the liver, a broad substrate selectivity, as well as inducibility by foreign compounds. The mEH is capable of inactivating a large number of structurally different, highly reactive epoxides and hence is an important part of the enzymatic defence of our organism against adverse effects of foreign compounds. Furthermore, evidence is accumulating that mammalian epoxide hydrolases play physiological roles other than detoxification, particularly through involvement in signalling processes. This certainly holds true for soluble epoxide hydrolase (sEH) whose main function seems to be the turnover of lipid derived epoxides, which are signalling lipids with diverse functions in regulatory processes, such as control of blood pressure, inflammatory processes, cell proliferation and nociception. In recent years, the sEH has attracted attention as a promising target for pharmacological inhibition to treat hypertension and possibly other diseases. Recently, new hitherto uncharacterised epoxide hydrolases could be identified in mammals by genome analysis. The expression pattern and substrate selectivity of these new epoxide hydrolases suggests their participation in signalling processes rather than a role in detoxification. Taken together, epoxide hydrolases (1) play a central role in the detoxification of genotoxic epoxides and (2) have an important function in the regulation of physiological processes by the control of signalling molecules with an epoxide structure.
环氧化物水解酶催化亲电（因此可能具有基因毒性）环氧化物水解为相应反应性较低的邻位二醇，这解释了环氧化物水解酶作为典型解毒酶的分类。最佳例子是哺乳动物微粒体环氧化物水解酶（mEH）——一种易于解毒的酶——因为它在肝脏中表达水平高、底物选择性广，且可被外源化合物诱导。mEH能够使大量结构不同的高反应性环氧化物失活，因此是我们机体针对外源化合物不良反应的酶防御的重要组成部分。此外，越来越多的证据表明，哺乳动物环氧化物水解酶除了解毒作用外还发挥生理作用，特别是通过参与信号传导过程。可溶性环氧化物水解酶（sEH）肯定是这样，其主要功能似乎是脂质衍生环氧化物的周转，这些环氧化物是在调节过程（如血压控制、炎症过程、细胞增殖和痛觉感受）中具有多种功能的信号脂质。近年来，sEH作为治疗高血压及可能其他疾病的有前景的药物抑制靶点受到关注。最近，通过基因组分析在哺乳动物中鉴定出了新的、迄今未表征的环氧化物水解酶。这些新环氧化物水解酶的表达模式和底物选择性表明它们参与信号传导过程而非解毒作用。总之，环氧化物水解酶（1）在基因毒性环氧化物的解毒中起核心作用，（2）通过控制具有环氧化物结构的信号分子在生理过程调节中具有重要功能。
